Two part hard shell capsule made of poly(1,4-alpha-d-glucan) and starch

ABSTRACT

The present invention relates to hard shell capsules consisting of two parts made from a poly(1,4-α-D-glucan)and starch based composition and the manufacturing thereof, preferentially by a dipping and pin molding process.

[0001] The present invention relates to hard shell capsules consistingof two parts made from a poly(1,4-α-D-glucan) and starch basedcomposition and the manufacturing thereof, preferentially by a dippingand pin moulding process.

[0002] Today, to produce satisfactory hard shell capsules gelatineand/or collagen, mostly in connection with plasticisers, are being used.Processes for there manufacture as well as such capsules themselves aredisclosed in e.g. U.S. Pat. No. 1,787,777; U.S. Pat. No. 3,032,700; U.S.Pat. No. 3,802,272; U.S. Pat. No. 4,026,986; U.S. Pat. No. 4,196,564;U.S. Pat. No. 4,250,007; U.S. Pat. No. 4,268,265; U.S. Pat. No.4,576,284; U.S. Pat. No. 4,738,817, Nduele et al., “The use of cassavastarch in hard gelatine capsule formulations.” J. Pharm. Belg. (1993),48(5), pp 325-34, WO 96/10996 and U.S. Pat. No. 4,780,316.

[0003] These two part hard shell capsules are mainly being processed insolution and melt moulding processes. Since gelatine and collagen are ofanimal origin and their consumption gives raise to hygienic and ethicalconcerns, in particular with respect to animal diseases like BSE (BovineSpongioforme Encephalopathy), nowadays products made from gelatineand/or collagen meet widespread rejection from customers, and it is upto now not clear whether there is a risk to sicken with BSE afterconsumption of such products.

[0004] Medicinal starch capsules consisting of two parts produced by abacking process from starch foam in a waffle mould were in use in thefirst part of the 20th century. These starch capsules were filled withthe active ingredient manually and are of insufficient mechanicalresistance to be used in modern filling automates.

[0005] Injection moulded two part starch capsules were disclosed e.g. inU.S. Pat. No. 4,738,818; U.S. Pat. No. 4,738,724; U.S. Pat. No.4,539,060; and U.S. Pat. No. 4,591,475. The capsules obtained in thisway were substantially consisting of amorphous starch whereuponbrittleness occurred and the capsules were not resistant to impact anddeformation in high performance filling units.

[0006] For the reasons above there have been many attempts in the art todevelop other hard shell capsules consisting of material from non animalorigin with satisfactory properties, at least with respect to mechanicalstrength. In JP 202003 capsules made of hemicellulose,carboxyrmethylcellulose or native starch, which are polysaccharides ofthe type poly(β-D-glucan) or poly(α-D-glucan), respectively, aredisclosed. In WO 00/18835 capsules consisting essentially of starchethers and oxydized starch are disclosed, whereas WO 96/10996 describescapsules based on I(iota)-carragenan. Water soluble cellulosederivatives for the manufacture of hard shell capsules in a dip mouldingprocess have been further suggested e.g. in U.S. Pat. No. 5,698,155 andU.S. Pat. No. 5,431,917. These substances are rather expensive, andtherefore this possibility is not generally accepted by capsuleconsumers. However, in spite of the so many attempts, none havesucceeded in manufacturing cellulose capsules or other capsules ofnon-animal origin in large quantities with sufficient uniformity to besuitable for filling in modern high-speed filling machines.

[0007] Thus, in the art no fully satisfactory hard shell capsulesconsisting of non-animal material have been described nor are theyavailable.

[0008] In view of the aforementioned facts there exists a high need inthe art to develop new hard shell capsules consisting essentially ofmaterial from non-animal origin as an excipient, these new capsulesbeing superior to capsules consisting essentially of material fromnon-animal origin already developed in the art at least with respect tomechanical strength.

[0009] Thus, it was one object of the present invention to provide hardshell capsules made from non-animal material, which should be highlyresistant to impact and deformation in order to be applicable in stateof the art high performance filling equipment, convenient for medicinaland cosmetic purposes, and these capsules should be superposable andtenable for prolonged periods of time.

[0010] Further objects of the present invention not explicitly mentionedhere can easily be derived from the aforementioned facts.

[0011] The solution to the above mentioned objects of the presentinvention is achieved by providing the embodiments as characterised inthe claims.

[0012] In one embodiment the present invention relates to two part hardshell capsules consisting essentially of a composition comprising

[0013] (a) at least 1% per weight poly(1,4-α-D-glucan) (based on thetotal carbohydrat contents of the present composition), and

[0014] (b) at the utmost 99% per weight starch (based on the totalcarbohydrat contents of the present composition), preferably chemicallymodified starch, and

[0015] (c) between 1 to 60% per weight based on the total carbohydratcontents of the present composition of a plasticiser,

[0016] wherein the poly(1,4-α-D-glucan) is characterised in that:

[0017] (i) the molar ratio of branched (1-4,-6)- and unbranched(1-4)-anhydroglucan units is ≦1×10⁻³,

[0018] (ii) the number average degree of polymerisation D(p)N lies inthe range between 40 and 300, and

[0019] (iii) the weight fraction of cristallinity f_(cystalline) is≧0.35.

[0020] and wherein the starch is characterised in

[0021] (iv) the number average degree of polymerisation D(p)N is ≧1×10²,and

[0022] (v) the molar ratio of branched (1-4,-6)- and unbranched(1-4)-anhydroglucan units is ≧0.2×10⁻², and

[0023] wherein the resulting Q_(branch) of the composition after mixingof (a) and (b) is ≧1×10⁻⁵.

[0024] Preferably, the present composition consists of 5-50% per weight,based on the carbohydrat-contents of the present composition,poly(1,4-α-D-glucan), more preferably 10-40%, mostly preferably 10-30%.

[0025] Preferably, the present composition consists of 50-95% perweight, based on the carbohydrat-contents of the present composition,starch, more preferably 60-90%, mostly preferably 70-90%.

[0026] Poly(1,4-α-D-glucan) is a polymer of α-D-anhydroglucan unitscoupled by α-1,4 semiacetalic bonds. The chemical structure of thedescribed polymer is a linear molecule in which the D-anhydroglucanunits are coupled by α-1,4 bonds between the carbon atom (1) and thecarbon atom (4) of the neighbouring anhydroglucan units.

[0027] From starch, poly(1,4-α-D-glucan)-structures with a certaindegree of 1-6 branching of anhydroglucan units are well known in theart, resulting in slightly branched molecules (amylose and amylopectin,respectively, with branching degrees from about >10⁻³ (amylose) up to3×10⁻²- 7×10⁻² (amylopectin)).

[0028] For the purposes of the present invention, branched units aredesignated “(1-4,-6) anhydroglucan units”, unbranched units aredesignated “(1-4) anhydroglucan units”.

[0029] Surprisingly the inventors found during the excessiveexperimentation that lead to the present invention that it is anessential feature of the poly(1,4-α-D-glucan) useful in the presentinvention that the molar ratio of the (1-4,-6) anhydroglucan units andthe (1-4) anhydroglucan units is limited.

[0030] It is assumed by the inventors that this is necessary to allowfor a sufficient occurrence of linear chain segments in the molecule,which could possibly play a role in recrystallization processes, butthis remains unclear.

[0031] For the purposes of the present invention, the molar ratiobetween (1-4,-6) anhydroglucan units and (1-4) anhydroglucan units isdesignated Q_(branch).

[0032] According to the present invention, the upper limiting value forQ_(branch) of the poly(1,4-α-D-glucan) is preferably 1×10⁻³, that is tosay the poly(1,4-α-D-glucan) molecules usable in the present inventionrange from molecules with Q_(branch) of 1×10⁻³ to molecules which arestrictly linear (Q_(branch)=0). More preferably the upper limiting valueis 1.5×10⁻⁴, and an even more preferred upper limiting value is1.5×10⁻⁵, and it is mostly preferred when the upper limiting value is1.5×10⁻⁶.

[0033] It has been found that in the composition of the presentinvention, strictly linear poly(1,4-α-D-glucan) molecules are bestsuited to arrive at fully satisfactory hard shell capsules. On the otherband, it was found that a slight degree of branching (up to 1×10⁻³) maybe tolerable in order to arrive at hard shell capsules with sufficientmechanical strength.

[0034] Q_(branch) is measured as described in: Hitzukuri, S.: “Starch:Analytical Aspects in Carbohydrates”, in Food, ed. by Eliasson, A.-Ch.,Marcel Decker Inc. NY, Basel, Hong Kong, 1996.

[0035] It was further found that the poly(1,4-α-D-glucan) useful in thepresent invention preferably has a number average degree ofpolymerisation D(p)N of at least 40, preferably this value lies in arange from 40 to 300 and more preferably in a range between 50-100.

[0036] The number average degree of polymerisation is defined as:

D(p)N=Σn _(i) ×Dp _(i) /Σn _(i)

[0037] wherein:

[0038] n_(i)=number of molecules with a given degree of polymerisation

[0039] Dp_(i)=given degree of polymerisation

[0040]_(i)=serial index

[0041] D(p)N is measured by GPC and MALDI-TOF, as described by C. Koch,“Methods for studying starch characteristics” PhD-Thesis 1999,Department of Food Science, Swedish University of Agricultural Science,Uppsala, No. Agraria 163.

[0042] Furthermore it has been found that the cristallinity of thepoly(1,4-α-glucan) usable in the present invention is correlated besidesothers with the linearity of the molecule (Q_(branch)) and therespective D(p)N of the molecule.

[0043] To be able to compare the crystallinity of different samples thefollowing standardised crystallisation process is used:

[0044] In a confined volume 5 g of the poly(1,4-α-D-glucan) sample isdissolved in 95 water at 137° C. and the solution is kept at thistemperature for 3 minutes. The solution is than cooled to 22° C. andkept for 48 hours at this temperature at 30% humidity. The resulting drysubstance is characterised by wide angle x-ray diffraction.

[0045] Methods to measure the cristallinity of a probe ofpolysaccharides can be found in Frech, D, J. Jpn. Soc. Starch, 1972 19,8and Zobel, H. F., Starch/Stärke 1988, 40, 1.

[0046] The resulting distribution of the intensity in arbitrary units asa function of the scattering angle is integrated between the limits ofintegration 5 to 35 degrees scattering angle and designated asI_(total).

[0047] The same procedure is done for the intensity distribution of thescattering by the crystallites and designated as I_(crystalline).

[0048] The quotient I_(crystalline)/I_(total)=f_(crystalline) is thecrystalline fraction or cristallinity of the sample.

[0049] It has been found that the cristallinity (f_(cristalline)) of thepoly(1,4-α-D-glucan) usable in the present invention should be at least0.35. More preferably, the value is ≧0.4 and a most preferred value is≧0.45.

[0050] As long as the aforementioned range of Q_(branch) and theaforementioned D(p)N as well as the mentioned f_(crystalline) areapplied, any poly(1,4-α-D-glucan) from any given source may be usedaccording to the invention.

[0051] Furthermore it has been found that the composition of the presentinvention is specially well suited for the intended purpose, if theresulting Q_(branch) after mixing together components (a) and (b) isequal to or above 1×10⁻⁵, a preferred value is equal to or above 1×10⁻⁴,it is more preferred when this value is equal to or above 1×10⁻⁴, and itis mostly preferred when this value is equal to or above b 1×10⁻².

[0052] In a preferred embodiment of the present invention thepoly(1,4-α-D-glucan) is produced by an enzymatic method using the enzymeamylosucrase disclosed in WO 95/31553.

[0053] In a further preferred embodiment of the present invention, thepoly(1,4-α-D-glucan) usable in the present invention is made from nativestarches, e.g. by enzymatic and/or chemical debranching methods wellknown in the art.

[0054] Furthermore, the poly(1,4-α-D-glucan) usable in the presentinvention may be obtained from animal sources like glycogen.

[0055] The poly(1,4-α-D-glucan) may as well be obtained from sourceslike e.g. bacteria, fungi or algae, which have been genetically modifiedin order to produce the above poly(1,4-α-D-glucan)s with low Q_(branch)values or which are strictly linear.

[0056] The poly(1,4-α-D-glucan) usable in the present invention may bechemically modified. These modifications can be accomplished e.g. byesterification, etherification or selective oxidation in 2-, 3- or6-Position.

[0057] For the purposes of the present invention, the term“modification” means that any free hydroxyl group of thepoly(1,4-α-D-glucan) can be used to introduce new chemical entities. Inprinciple any modification described in greater detail later on in thecontext of the starch component of the present composition may beapplied to the poly(1,4-α-D-glucan) as well.

[0058] Unmodified poly(1,4-α-D-glucan) is preferred.

[0059] The above described poly(1,4-α-D-glucan) shows a remarkablypronounced tendency to generate structures with regular conformation,e.g. double helices and shows a high degree of cristallinity, what canbe shown by X-ray diffraction and 13 C nuclear magnetic resonance.

[0060] It is assumed by the authors that due to this tendency the abovepoly(1,4-α-D-glucan) is specially well suited as an essential ingredientof the composition according to the present invention.

[0061] As a result of the above defined characteristics of the preferredpoly(1,4-α-D-glucan), specially with respect to D(p)N and Q_(branch)this polyglucan shows a pronounced tendency to be water-insoluble.

[0062] The water insolubility of the poly(1,4-α-D-glucan) used accordingto the invention is expediently such that at least 98%, in particular atleast 99.5% of the poly(1,4-α-D-glucan) used are water-insoluble understandard conditions (T=25° C., p=101325 Pascal ), in accordance withclasses 4-7 of the German Pharmacopae DAB, WissenschaftlicheVerlagsbuchhandlung mbH, Stuttgart, Govi-Verlag GmbH, Frankfurt, 9^(th)edition 1987).

[0063] These classes correspond to the categories sparingly soluble,slightly soluble, very slightly soluble and practically insoluble.

[0064] In addition to other advantages of the two part hard shellcapsule of the invention, the inventors found that by using such anwater-insoluble poly(1,4-α-D-glucan) as part of the composition used toproduce said capsule, one can easily produce hard shell capsules withremarkably decreased tendency of water-immigration/-sorption and withreduced hygroscopicity, which results in an improved shelf life anddurability of the ready-made product, e.g. capsule plus activeingredient.

[0065] For example, the hygroscopicity of the ready-made product, e.g.the capsule of the present invention, may be determined by measuring theincrease in weight of the capsule over the time in an atmosphere withdefined water concentration. These methods are very well known to thoseskilled in the art.

[0066] The occurrence of such an advantageous effect was surprising,since it is sufficient if only the poly(1,4-α-D-glucan) portion of thecomposition is water-insoluble, whereas the other, starch-part of thecomposition is not.

[0067] Therefore, it is preferred that the poly(1,4-α-D-glucan) usedaccording to the invention belongs to classes 4-7 of the DAB. It is morepreferred if the poly(1,4-α-D-glucan) belongs to classes 5-7 of the DAB.Even more preferred the poly(1,4-α-D-glucan) belongs to classes 6-7 ofthe DAB.

[0068] The other main component of the composition of the invention isstarch, either native or chemically modified.

[0069] Starches preferably useful in the present invention have a numberaverage degree of polymerisation D(p)N≧10² and the respective Q_(branch)is ≧1×10⁻⁶, preferably ≧1×10⁻⁴ and mostly preferred ≧2×10⁻³.

[0070] Therefore, the starches preferably usable in the presentinvention can easily be distinguished from the poly(1,4-α-D-glucan)which forms the other main component of the composition of the presentinvention, since the poly(1,4-α-D-glucan) usable in the presentinvention has a Q_(branch)≦10⁻³.

[0071] According to the present invention, any starch can be used aslong as the above D(p)N>10² and Q_(branch)≧2×10⁻³ is applied. Alsomixtures of different types of starches can be applied. Examples ofstarches which can be used according to the present invention comprise,inter alia, starch from tubers, such as potatoes, cassava, tapioca,maranta, sweet potato, from seeds such as wheat, corn, rye, rice,barley, millet, oats, sorghum, from fruits such as chestnuts, acorns,beans, peas and other legumes, banana and from plant piths, e.g. of thesago palm.

[0072] The starches usable in the present invention consist essentiallyof amylose and amylopectin in varying ratios.

[0073] According to the present invention, the term “modified starch”means any starch which was altered in order to change their propertiesor behaviour under different circumstances. The modifications introducedcomprise altering the amylose/amylopectin ratio, gelatinization prior touse, partial hydrolytic or enzyme-based degradation or introduction ofnew chemical entities.

[0074] Specially, modified starches are starches with newly introducedchemical groups, e.g. dialdehyde-starches, carboxy-starches,hydroxypropylated starches or native starches with introduced cationicand/or anionic side groups. Chemically modified starches are well knownin the art.

[0075] The modification thus is mainly achieved by reactions on thepolymer, in which starch is treated with mono- or polyfunctionalreagents or oxidizing agents. This preferably entails the hydroxylgroups of the polyglucans of the starch being. converted byesterification, etherification or selective oxidation. Anotherpossibility consists of graft copolymerization, initiated by freeradicals, of copolymerizable unsaturated monomers onto the starchbackbone.

[0076] Particular chemically modified starches include, inter alia,starch esters such as xanthates, acetates, phosphates, sulfates,nitrates, starch ethers such as, e.g., non-ionic, anionic or cationicstarch ethers, oxidized

[0077] It was found that in order to produce hard shell capsules fromthe above mentioned composition, it is necessary that at least 1% perweight of the resulting composition is represented by thepoly(1,4-α-D-glucan). An upper limiting value is 99% per weight.

[0078] The same applies for the starch component of the presentinvention.

[0079] As long as the above values are maintained, the composition ofthe present invention can be used to produce hard shell capsules withimproved properties. It was found by the authors of the presentinvention that the resulting composition is specially well suited forthe production of hard shell capsules, if the resulting mean valueQ_(branch(total)) of the composition of the invention after mixing thepoly(1,4-α-D-glucan) and the starch component, respectively, is equal orabove 2×10⁻³.

[0080] A third essential component of the composition of the presentinvention is a plasticiser. The plasticiser can be chosen from the groupconsisting of water; polyalcohols as e.g. ethylene glycol, glycerol,propanediol, erythriol, mannitol, sorbitol; multivalent aliphaticcarbonic acids as e.g. maleic acid, succinic acid; multivalenthydroxyaliphatic carbonic acids as e.g. lactic acid, 2-hydroxybutanoicacid, citric acid, malic acid; dimethyl sulfoxide, urea or otherstarch-solvents.

[0081] Of this group, preferred plasticisers are water and glycerol.Specially preferred is water.

[0082] Although a plasticiser is needed in order to work the presentinvention, the nature of the plasticiser is not as important as theabove described components (a) and (b) of the composition of the presentinvention. On the other hand, as the hard shell capsules of the presentinvention are mainly intended for medicinal and cosmetic use, i. e. fororal administration, it is clear to one skilled in the art of makingcapsules, that this plasticiser should be per se edible, i.e. non toxic.Therefore, any edible, non-toxic solvent for starch known in the art maybe used as a plasticiser according to the invention. For the samereasons, water is the preferred plasticiser according to the invention.

[0083] For one skilled in the art it becomes clear that mixtures ofplasticisers may be used without leaving the scope of the invention.

[0084] Besides the aforementioned essential components (a), (b) and (c)the composition of the present invention may further comprise additives,e.g. lubricants, fillers and flavouring substances. These additives maybe added depending on the intended use of the capsule. The respectiveadditives are well known in the art, and there is no need to list themhere.

[0085] Surprisingly the inventors found that mixtures ofpoly(1,4-α-D-glucan) synthesised by the enzyme amylosucrase from sucrosein vitro as disclosed in WO 95/31553 and starch, preferably modifiedstarch, give layers of high mechanical flexibility and strength oncoating and drying from their aqueous solutions.

[0086] Films shaped to capsules from mixtures comprisingpoly(1,4-α-D-glucan) and modified starch were prepared with highthroughput filling equipment normally used to make hard gelatinecapsules consisting of two parts by a pin dipping and moulding process.

[0087] It was further found that the mechanical properties of the filmscan be improved by additives, e.g. fillers and lubricants.

[0088] Recrystallisation of the poly(1,4-α-D-glucan) and starchcomposition takes place during cooling and drying of the solution coatedon the pin mould in the capsule forming process. It is assumed by theinventors that due to the fast recrystallisation (circa 10-20 seconds)of the composition of the present invention consisting essentially ofpoly(1,4-α-D-glucan) and starch coated on the pins in the pin mouldingprocess an aqueous gel is formed, stabilising the coated layer andallowing the movement of air in the drying section of the mouldingmachine. In the absence of an elastic gel phase the movement of thedrying air would deform the coated aqueous layer. The fast formation ofthe elastic gel phase of the aqueous solution of poly(1,4-α-D-glucan)and starch allows stable layer formation and stabilisation during thedrying process.

[0089] This may be an explanation for the surprising fact thatcompositions with at least a certain degree of the above definedpoly(1,4-α-D-glucan) and starch are able to build films that aresufficiently stable in order to be used to produce the hard shellcapsules of the present invention, since it is assumed that the fastrecristallization is depending on the linear or at least showing only avery little degree of branching and rather small (small Dp(N))poly(1,4-α-D-glucan) molecules usable in the present invention.

[0090] The dip moulding machine usable in the present invention consistsof a container for solutions of the capsule shell material, pin barscarrying the pin shaped mould, the mechanism transporting the pin barsin the machine, hoods with inlets and outlets for air with controlledhumidity (the humidity of air at temperature T is expressed in weight %of the humidity of air saturated with water vapour at temperature T) andtemperature. Devices to cut off the open edge of the capsule shells onthe pin mould and the release of the capsule shells from the mould. Thismachine is described in detail in U.S. Pat. No. 1,787,777. In theconventional hard shell capsule process aqueous solution of gelatine andadditives is placed into the container and the pins are coated with alubricant and set to a selected temperature. The transport mechanism forthe mould bars enters the pins directed downwards into the gelatinesolution and removes them after selected duration for the coating. Thepin bars are then rotated by even integers for the number of halfrotations resulting upwards oriented pins on the bars which aretransported into the space covered by the first hood. Circulation of airis maintained around the pins coated with the gelatine solution. The pinbars are continuously transported into the space covered by furtherhoods. The temperature and level of the gelatine solution in thecontainer, the humidity and temperature in the hoods and the speed oftransport of the pin bars are controlled. The open end of the capsuleshell is cut off on the pin and the shells are released from the pins.The mould bars are then cleaned in an automatic process and reintroducedinto the mould process.

[0091] In the present invention the specifications for the solutions,temperatures, air humidity and speeds of transport are adapted to thecomposition containing poly(1,4-α-D-glucan) and starch replacing thegelatine in the aqueous solution placed into the container of thecapsule making machine:

[0092] Weight fraction of the poly(1,4-α-D-glucan) in the appliedaqueous solution is in the range 0.01-0.7, preferentially is in therange 0.05-0.5, more preferentially is in the range 0.1-0.2.

[0093] Poly(1,4-α-D-glucan) and starch are dissolved in water andadditives at temperatures T1 in the range 50<T1<180° C., preferentiallyin the range 50<T1<100° C.

[0094] The aqueous solution of the poly(1,4-α-D-glucan) and starchcomposition is kept in the container at controlled values of temperatureT2 in the range 50<T2<95° C.

[0095] The temperature T3 and humidity h1 of the air circulating in thefirst hood in order to allow for controlled cooling of the aqueoussolution coated on the pins of the pin dipping and moulding machine iskept at controlled values in the ranges 10<T3<140° C. and 5<h1<99%.

[0096] The temperature T4 and humidity h2 of the air circulating in thesecond hood in order to allow for controlled cooling of the aqueoussolution coated on the pins of the pin dipping and moulding machine iskept at controlled values in the ranges 10<T4<135° C. and 5<h2<95%.

[0097] The temperature T5 and humidity h3 of the air circulating in thethird hood in order to allow for controlled cooling of the aqueoussolution coated on the pins of the pin dipping and moulding machine iskept at controlled values in the ranges 10<T5<130° C. and 5<h3<90%.

[0098] The temperature T6 and humidity h4 of the air circulating in thefourth hood in order to allow for controlled cooling of the aqueoussolution coated on the pins of the pin dipping and moulding machine iskept at controlled values in the ranges 10<T6<125° C. and 5<h4<85%.

[0099] The temperature T7 and humidity h5 of the air circulating in thefifth hood in order to allow for controlled cooling of the aqueoussolution coated on the pins of the pin dipping and moulding machine iskept at controlled values in the ranges 10<T6<120° C. and 5<h4<80%.

[0100] Transport of the pin bars through the machine is set to speeds toachieve for the

[0101] duration of coating in lasts 0.1 to 30 seconds, preferentially 1to 10 seconds;

[0102] duration of the rotation lasts 0.1 to 10 seconds, preferentially1 to 3 seconds;

[0103] duration for the cooling of the pin bars in the five hoods lasts5 to 50 minutes, preferentially 20 to 40 minutes.

[0104] The poly(1,4-α-D-glucan) based composition may further compriseother polysaccharides, polyesters, fats, proteins and derivativesthereof, preferentially of plant, microbiological or biotechnologicalorigin, which optionally may be further modified by e.g. hydrolysisand/or reduction, respectively. It is preferred that the amount of waterin the capsule shell made from the aforementioned composition varies inthe range of 0.005 to 0.2% per weight, more preferred 0.02 to 0.1% perweight corresponding to the thermodynamic equilibrium with thesurrounding atmosphere.

[0105] In said water content range the capsules may be kept for severalyears without damage. The capsules consist of an upper cover part and alower part to accommodate the active ingredients, and they aremechanically resistant to impact and deformation in widespread used highperformance capsule filling equipment. The capsules made from thecomposition of the invention show an increased barrier effect againstadditional water immigration or atmospheric gas transfer anddisintegrate under physiological conditions within short time to releasethe encapsulated material.

[0106] The capsules may be used to any encapsulation purpose, and theyare specially suited for pharmaceutical and/or cosmetic and/or food,food additive or food supplement or food ingredient purposes.

[0107] Furthermore, the capsules are especially well suited forencapsulation of fragrances or colorants/dyes, e.g. in the form ofpaintballs.

[0108] To illustrate the invention the following non-limiting examplesand comparative examples are provided.

[0109] As comparative examples native starches with amylose content <70%per weight and water soluble chemically substituted starches madetherefrom were dissolved in water and used in the dip moulding processaccording to the present invention. These resulted in a film withinsufficient mechanical resistance towards forces generated during themanufacturing steps of the dip moulding process: drying and mouldreleasing. The resulting films were brittle on deformation. The sameinsufficient properties were observed when the two part capsules aremade in an injection moulding process, no matter if the appliedcomposition contains poly(1,4-α-D-glucan) or not.

EXAMPLE 1

[0110] Poly(1,4-α-D-glucan) characterised by Q_(branch)<10⁻⁶,f_(crystalline)=0.45 and D(p)N=80, and potato starch (about 80%amylopectin) was used to produce capsules. 10% per weightpoly(1,4-α-D-glucan) was combined with 90% per weight Amyloplast PE 004.To 1 kg of this composition 0.2 kg of plasticiser containing glycerol,sorbitol and other sugar alcohols prepared by reduction of sugars wasadded and dissolved with 8.8 kg water at 140° C. in confined volume. Thesolution of poly(1,4-α-D-glucan), starch and plasticiser was kept at 90°C. for 2 hours and transferred to the container in a dip mouldingmachine. Temperature of the container for the starch solution was 90° C.The dip moulding machine to produce the capsule shells was equipped withpin bars carrying ten pins of length 20 cm and diameter 4 cm. Thetransport of the pin bars was selected to give 30 minutes for thecoating, drying, cutting and mould release. The coated pins weretransported through 5 hoods with temperatures of drying air 65, 40, 25,20 and 15° C.; the humidity of the drying air were 60, 50, 30, 20 and10%. The resulting capsules were cut into strips and the elongation andstress at brake was determined (see table 1).

EXAMPLE 2

[0111] 5% per weight of the poly(1,4-α-D-glucan) of example 1 wascombined with 95% per weight of the potato starch and this compositionwas used in this example in the otherwise same procedure as inexample 1. The mechanical properties of the produced films are given intable 1.

EXAMPLE 3

[0112] 15% per weight of the poly(1,4-α-D-glucan) of example 1 wascombined with 85% per weight of the potato starch and this compositionwas used in this example in the otherwise same procedure as inexample 1. The mechanical properties of the produced films are given intable 1.

COMPARATIVE EXAMPLE 1

[0113] The potato starch was replaced by poly(1,4-α-D-glucan) of example1 in the otherwise same procedure as in example 1. The mechanicalproperties of the produced films are given in table 1.

COMPARATIVE EXAMPLE 2

[0114] The poly(1,4-α-D-glucan) of example 1 was replaced by the potatostarch in this example in the otherwise same procedure as in example 1.The mechanical properties of the produced films are given in table 1.TABLE 1 Results of examples 1-3 and comparative examples 1-2 stress[MPA] strain No. of at brake of film samples example f_(cristalline)Q_(branch)** D(p)N of capsule shell Example 1 n.d.  0.9 × 10⁻² 3800 301.5 Example 2 n.d. 0.95 × 10⁻² 3900 20 1.2 Example 3 n.d. 0.85 × 10⁻²3700 50 1.7 Comparative 0.45 0 80 * * Example 1 Comparative 0.02 10⁻²4000 <1 <1.05 Example 2

[0115] The results of examples 1 to 3 show that a combination ofpoly(1,4-α-D-glucan) and potato starch (Amyloplast™) results in filmsuseful in the applied process for making hard shell two part capsules.The results of the comparative examples 1 and 2 show that neitherpoly(1,4-α-D-glucan) nor Amyloplast alone result in useful films in theapplied process for making hard shell two part capsules. Furthermore,the resulting mechanical properties of the dry layers of the capsuleshells—their elongation at least 1.2 and stress at least 20 MPA atbreak—are fulfilling the recommendations for their applicability.

1. Two part hard shell capsule, the shell consisting essentially of acomposition comprising (a) at least 1% per weight poly(1,4-α-D-glucan),based on the total carbohydrate content of the composition, and (b) atthe utmost 99% per weight starch, based on the total carbohydratecontent of the composition, preferably chemically modified starch,together with (c) between 1 to 60% per weight of a plasticiser, based onthe total carbohydrate content of the composition, wherein thepoly(1,4-α-D-glucan) (a) is characterised in: (i) the molar ratio ofbranched (1-4,-6)- and unbranched (1-4)-anhydroglucan units is <1×10⁻³,(ii) the number average degree of polymerisation D(p)N lies in the rangebetween 40 and 300, and (iii) the weight fraction of cristallinityf_(crystalline) is >0.35. and wherein the starch (b) is characterised in(iv) the number average degree of polymerisation D(p)N is >10², and (v)the molar ratio of branched (1-4,-6)- and unbranched (1-4)-anhydroglucanunits is >0.2×10⁻², and wherein (vi) the resulting Q_(branch) of thecomposition after mixing of (a) and (b) is ≧1×10⁻⁵.
 2. Two part hardshell capsule according to claim 1, the resulting Q_(branch) (vi) of thecomposition after mixing of (a) and (b) being ≧0.2×10⁻².
 3. Two parthard shell capsule according to claim 1, the molar ratio of item (i) ofbranched (1-4,-6)- and unbranched (1-4)-anhydroglucan units is<1.5×10⁻⁴, preferably <1.5×10⁻⁵.
 4. Two part hard shell capsuleaccording to claim 1, the Dp(N) of item (ii) being from 50 to
 100. 5.Two part hard shell capsule according to claim 1, the f_(crystalline) ofitem (iii) being ≧0.4, preferably ≧0.45.
 6. Two part hard shell capsuleaccording to claim 1, the starch fraction (b) being 50-90% per weight,based on the carbohydrat-contents of the composition, starch, preferably60-90% per weight, mostly preferably 70-90% per weight.
 7. Pin dippingand moulding process for the production of a two part hard shell capsuleaccording to claim
 1. 8. Use of the capsule according to claim 1 for thepreparation of a medical preparation.
 9. Two part hard shell capsuleaccording to claim 1 containing a food additive, supplement oringredient.
 10. Two part hard shell capsule according to claim 1containing pharmaceutically active ingredients.